Thyroid hormone receptor beta inhibits the PI3K-Akt-mTOR signaling axis in anaplastic thyroid cancer via genomic mechanisms

Abstract

Thyroid cancer is the most common endocrine malignancy, and the global incidence has increased rapidly over the past few decades. Anaplastic thyroid cancer (ATC) is highly aggressive, dedifferentiated, and patients have a median survival of fewer than six months. Oncogenic alterations in ATC include aberrant PI3K signaling through receptor tyrosine kinase (RTK) amplification, loss of phosphoinositide phosphatase expression and function, and Akt amplification. Furthermore, the loss of expression of the tumor suppressor thyroid hormone receptor beta (TRβ) is strongly associated with ATC. TRβ is known to suppress PI3K in follicular thyroid cancer and breast cancer by binding to the PI3K regulatory subunit p85α. However, the role of TRβ in suppressing PI3K signaling in ATC is not completely delineated. Here we report that TRβ indeed suppresses PI3K signaling in ATC through unreported genomic mechanisms including a decrease in RTK expression and increase in phosphoinositide and Akt phosphatase expression. Furthermore, the reintroduction and activation of TRβ in ATC enables an increase in the efficacy of the competitive PI3K inhibitors LY294002 and buparlisib on cell viability, migration, and suppression of PI3K signaling. These findings not only uncover additional tumor suppressor mechanisms of TRβ but shed light into the implication of TRβ status and activation on inhibitor efficacy in ATC tumors.Abstract FigureGraphical abstract

Thyroid Hormone Receptor Beta Inhibits PI3K-Akt-mTOR Signaling Axis in Anaplastic Thyroid Cancer via Genomic Mechanisms

“…4C ). These findings illustrate the trend between TRβ and expression of tumor suppressive genes in PI3K signaling in a genetically diverse set of ATC cell lines (Supplementary Table 3 [ 28 ]).…”

“…In addition to these genes that serve to regulate PI3K activation and subsequent Akt phosphorylation, genes involved in PI3K recruitment and stabilization, mTORC regulation, and translation factors were found to be differentially regulated in the TRβ-T 3 group (Supplementary Fig. 1A-1D and Table 2 [ 28 ]). The fold change of a subset of the differentially expressed genes was validated via reverse transcriptase–quantitative polymerase chain reaction (Supplementary Fig.…”

“…The fold change of a subset of the differentially expressed genes was validated via reverse transcriptase–quantitative polymerase chain reaction (Supplementary Fig. 2 [ 28 ]).…”

“…Even in the presence of full serum and activated RTKs, the TRβ group rendered the SW1736 cells less viable (Supplementary Fig. 3A and 3B [ 28 ]). In accordance with the RNA-seq data, T 3 is necessary for maximum inhibition of cell viability by TRβ.…”

“…Fold change in gene expression compared to endogenous controls was calculated using the ddCT method. Primer sequences are indicated in Supplementary Table 1 [ 28 ].…”